ABSTRACT Hydrocephalus is a disorder of cerebral spinal fluid (CSF) physiology that results in progressive expansion of cerebral ventricles and elevated intracranial pressure (ICP). It affects 1-2 of every 1000 live births, making it the most common disease treated by pediatric neurosurgeons in the US. The usual treatment is neurosurgical shunt placement to divert CSF and relieve elevated ICP. Decision-making about when and if to intervene is mostly based on imaging evidence of enlarged ventricular size and clinical judgement. Ventricular size, however, is a suboptimal surrogate of elevated ICP and ischemia. Indeed, roughly 15% of patients experiencing elevated ICP do not have CT imaging evidence of increased ventricle size. The inconsistent relationship between ICP and ventricular size increases the risk of prolonged intracranial hypertension, ischemia, and secondary brain damage occurring prior to surgical treatment. The primary goals of this proposal are to: (1) develop and validate a novel diffuse optical approach for non- invasive detection of elevated ICP and cerebral ischemia; and (2) use multimodal longitudinal diffuse optical measures of cerebral hemodynamics to identify risk factors for the development of elevated ICP. Diffuse optics techniques provide a wealth of multimodal cerebral hemodynamic data continuously, non-invasively, and at the bedside. Specifically, diffuse optics technology can measure indices of cerebral blood flow (CBF), oxygen extraction fraction (OEF), and oxygen metabolism (CMRO2). The principal investigator (PI) has also pioneered a novel optical approach for assessment of elevated ICP. The approach is based on measurement of cerebral critical closing pressure (CrCP) with near-infrared light intensity correlations. CrCP is the sum of ICP and active arteriolar wall tension, and its name reflects the notion that arterioles close and CBF ceases when arterial blood pressure falls below the CrCP threshold. This proposal will use diffuse optics to measure longitudinal hemodynamics of brain physiology during progressive ventricular enlargement in a large group of children (Aim 1). The multimodal data will be related to invasive intraoperative ICP measurements for: (1) identification of preoperative risk factors of elevated ICP; and (2) validation of elevated CrCP as a metric of elevated ICP. Diffuse optical neuro-monitoring will further be compared to invasive neuro-monitoring in a pediatric piglet model of intracranial hypertension to develop optical biomarkers of ischemia and elevated ICP (Aim 2). In Aim 3, diffuse optics will be translated for diagnosing shunt failure in older children, which occurs in 40% of patients within 2 years of age. The proposal?s interdisciplinary team of physical scientists and clinicians provides leading expertise in diffuse optics, piglet model research, and hydrocephalus care. Ultimately, by allowing the timing of surgical intervention to be optimized and individualized for each patient, diffuse optics promises to substantially reduce or prevent secondary brain damage from hydrocephalus.